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1.  Coactosin-Like 1 Antagonizes Cofilin to Promote Lamellipodial Protrusion at the Immune Synapse 
PLoS ONE  2014;9(1):e85090.
Actin depolymerizing factor-homology (ADF-H) family proteins regulate actin filament dynamics at multiple cellular locations. Herein, we have investigated the function of the ADF-H family member coactosin-like 1 (COTL1) in the regulation of actin dynamics at the T cell immune synapse (IS). We initially identified COTL1 in a genetic screen to identify novel regulators of T cell activation, and subsequently found that it associates with F-actin and localizes at the IS in response to TCR+CD28 stimulation. Live cell microscopy showed that depletion of COTL1 protein impaired T cell spreading in response to TCR ligation and abrogated lamellipodial protrusion at the T cell – B cell contact site, producing only a band of F-actin. Significantly, re-expression of wild type COTL1, but not a mutant deficient in F-actin binding could rescue these defects. In addition, COTL1 depletion reduced T cell migration. In vitro studies showed that COTL1 and cofilin compete with each other for binding to F-actin, and COTL1 protects F-actin from cofilin-mediated depolymerization. While depletion of cofilin enhanced F-actin assembly and lamellipodial protrusion at the IS, concurrent depletion of both COTL1 and cofilin restored lamellipodia formation. Taken together, our results suggest that COTL1 regulates lamellipodia dynamics in part by protecting F-actin from cofilin-mediated disassembly.
PMCID: PMC3890291  PMID: 24454796
2.  Finding the probability of infection in an SIR network is NP-Hard 
Mathematical biosciences  2012;240(2):77-84.
It is the purpose of this article to review results that have long been known to communications network engineers and have direct application to epidemiology on networks. A common approach in epidemiology is to study the transmission of a disease in a population where each individual is initially susceptible (S), may become infective (I) and then removed or recovered (R) and plays no further epidemiological role. Much of the recent work gives explicit consideration to the network of social interactions or disease-transmitting contacts and attendant probability of transmission for each interacting pair. The state of such a network is an assignment of the values {S, I, R} to its members. Given such a network, an initial state and a particular susceptible individual, we would like to compute their probability of becoming infected in the course of an epidemic. It turns out that this and related problems are NP-hard. In particular, it belongs in a class of problems for which no efficient algorithms for their solution are known. Moreover, finding an efficient algorithm for the solution of any problem in this class would entail a major breakthrough in theoretical computer science.
PMCID: PMC3478503  PMID: 22824138
epidemics; SIR networks; contact network; network reliability; NP-hard
3.  The Cycle of EBV Infection Explains Persistence, the Sizes of the Infected Cell Populations and Which Come under CTL Regulation 
PLoS Pathogens  2013;9(10):e1003685.
Previous analysis of Epstein-Barr virus (EBV) persistent infection has involved biological and immunological studies to identify and quantify infected cell populations and the immune response to them. This led to a biological model whereby EBV infects and activates naive B-cells, which then transit through the germinal center to become resting memory B-cells where the virus resides quiescently. Occasionally the virus reactivates from these memory cells to produce infectious virions. Some of this virus infects new naive B-cells, completing a cycle of infection. What has been lacking is an understanding of the dynamic interactions between these components and how their regulation by the immune response produces the observed pattern of viral persistence. We have recently provided a mathematical analysis of a pathogen which, like EBV, has a cycle of infected stages. In this paper we have developed biologically credible values for all of the parameters governing this model and show that with these values, it successfully recapitulates persistent EBV infection with remarkable accuracy. This includes correctly predicting the observed patterns of cytotoxic T-cell regulation (which and by how much each infected population is regulated by the immune response) and the size of the infected germinal center and memory populations. Furthermore, we find that viral quiescence in the memory compartment dictates the pattern of regulation but is not required for persistence; it is the cycle of infection that explains persistence and provides the stability that allows EBV to persist at extremely low levels. This shifts the focus away from a single infected stage, the memory B-cell, to the whole cycle of infection. We conclude that the mathematical description of the biological model of EBV persistence provides a sound basis for quantitative analysis of viral persistence and provides testable predictions about the nature of EBV-associated diseases and how to curb or prevent them.
Author Summary
Epstein-Barr virus (EBV) is a herpesvirus that establishes a lifelong persistent infection in virtually all human beings. This infection is a risk factor for the subsequent development of certain tumors and possibly also autoimmune diseases. In order to understand the origin of these diseases, it is necessary to first understand how EBV maintains persistent infection. We have used mathematical analysis to study this question. We find that the characteristic cycle of infected stages that EBV establishes in vivo allows it to persist stably at extremely low levels. This represents a consistent mathematical description of EBV infection and allows us to describe what must change to convert benign infection into pathogenic infection, as well as what kind of efficacy drugs and vaccines must have in order to be useful.
PMCID: PMC3798424  PMID: 24146621
4.  Zonisamide for Weight Loss in Adolescents 
Obesity in children and adolescents is a growing epidemic in the United States, and physicians are increasingly looking for safe and effective treatments. In recent years, pharmacologic treatment has been considered for severe and refractory cases of adolescent obesity. We present a case of an obese adolescent who presented to an inpatient psychiatric unit with a body mass index (BMI) of 37.8 (>98th percentile for age). He was started on zonisamide for the purposes of weight loss, and a steady decrease in weight and BMI was noted through 4 months of outpatient follow-up. During this time, the patient's weight decreased from 126.8 kg to 106.2 kg, a 20.6-kg loss, representing a 16.25% reduction in weight. His most recent BMI decreased to 31.7 (96th percentile for age). We discuss the potential use of zonisamide for weight loss in adolescents, considering the potential risks and benefits.
PMCID: PMC3979054  PMID: 24719592
adolescents; antiobesity agents; obesity; weight loss; zonisamide
5.  Genomic diversity and evolution of the head crest in the rock pigeon 
Science (New York, N.Y.)  2013;339(6123):1063-1067.
The geographic origins of breeds and genetic basis of variation within the widely distributed and phenotypically diverse domestic rock pigeon (Columba livia) remain largely unknown. We generated a rock pigeon reference genome and additional genome sequences representing domestic and feral populations. We find evidence for the origins of major breed groups in the Middle East, and contributions from a racing breed to North American feral populations. We identify EphB2 as a strong candidate for the derived head crest phenotype shared by numerous breeds, an important trait in mate selection in many avian species. We also find evidence that this trait evolved just once and spread throughout the species, and that the crest originates early in development by the localized molecular reversal of feather bud polarity.
PMCID: PMC3778192  PMID: 23371554
6.  Fluorescein angiography to estimate normal peripheral retinal nonperfusion in children 
To estimate the normal distance from vascular termini to ora serrata in children’s eyes.
Clinical records and peripheral fluorescein angiography images of the ora serrata region, taken using scleral indentation and the RetCam system during examination under anesthesia, were retrospectively reviewed from 33 eyes of 31 consecutive patients with presumed normal peripheral retinal vasculature. All patients had ocular disease either only in the fellow eye or if in the study eye, to a degree judged not likely to affect peripheral retinal vascular development.
The mean age at angiography was 3.8 years (range, 2 months to 13 years). Means of 0.9 disk diameters (DD) of nonperfusion temporally (range, 1.5 DD to 0.5 DD; SD 0.3) and 0.6 DD of nonperfusion nasally (range, 1 DD to 0.25 DD; SD 0.2) were found.
In children up to age 13 years, the avascular retina normally extends 1.5 DD or less temporally and 1.0 DD or less nasally from the ora serrata. Conservatively, ≥2 DD of nonperfusion, 3 standard deviations more than normal, should be considered abnormal and a sign of peripheral nonperfusion. These data may serve as preliminary indicators of the range of normal when evaluating diseases with retinal vascular abnormalities in children.
PMCID: PMC3756139  PMID: 22681939
7.  A Val85Met Mutation in Melanocortin-1 Receptor Is Associated with Reductions in Eumelanic Pigmentation and Cell Surface Expression in Domestic Rock Pigeons (Columba livia) 
PLoS ONE  2013;8(8):e74475.
Variation in the melanocortin-1 receptor (Mc1r) is associated with pigmentation diversity in wild and domesticated populations of vertebrates, including several species of birds. Among domestic bird species, pigmentation variation in the rock pigeon (Columbalivia) is particularly diverse. To determine the potential contribution of Mc1r variants to pigment diversity in pigeons, we sequenced Mc1r in a wide range of pigeon breeds and identified several single nucleotide polymorphisms, including a variant that codes for an amino acid substitution (Val85Met). In contrast to the association between Val85Met and eumelanism in other avian species, this change was associated with pheomelanism in pigeons. In vitro cAMP accumulation and protein expression assays revealed that Val85Met leads to decreased receptor function and reduced cell surface expression of the mutant protein. The reduced in vitro function is consistent with the observed association with reduced eumelanic pigmentation. Comparative genetic and cellular studies provide important insights about the range of mechanisms underlying diversity among vertebrates, including different phenotypic associations with similar mutations in different species.
PMCID: PMC3744500  PMID: 23977400
8.  Comparison of Traditional Cardiovascular Risk Models and Coronary Atherosclerotic Plaque as Detected by Computed Tomography for Prediction of Acute Coronary Syndrome in Patients With Acute Chest Pain 
The objective was to determine the association of four clinical risk scores and coronary plaque burden as detected by computed tomography (CT) with the outcome of acute coronary syndrome (ACS) in patients with acute chest pain. The hypothesis was that the combination of risk scores and plaque burden improved the discriminatory capacity for the diagnosis of ACS.
The study was a subanalysis of the Rule Out Myocardial Infarction Using Computer-Assisted Tomography (ROMICAT) trial—a prospective observational cohort study. The authors enrolled patients presenting to the emergency department (ED) with a chief complaint of acute chest pain, inconclusive initial evaluation (negative biomarkers, nondiagnostic electrocardiogram [ECG]), and no history of coronary artery disease (CAD). Patients underwent contrast-enhanced 64-multidetector-row cardiac CT and received standard clinical care (serial ECG, cardiac biomarkers, and subsequent diagnostic testing, such as exercise treadmill testing, nuclear stress perfusion imaging, and/or invasive coronary angiography), as deemed clinically appropriate. The clinical providers were blinded to CT results. The chest pain score was calculated and the results were dichotomized to ≥10 (high-risk) and <10 (low-risk). Three risk scores were calculated, Goldman, Sanchis, and Thrombolysis in Myocardial Infarction (TIMI), and each patient was assigned to a low-, intermediate-, or high-risk category. Because of the low number of subjects in the high-risk group, the intermediate- and high-risk groups were combined into one. CT images were evaluated for the presence of plaque in 17 coronary segments. Plaque burden was stratified into none, intermediate, and high (zero, one to four, and more than four segments with plaque). An outcome panel of two physicians (blinded to CT findings) established the primary outcome of ACS (defined as either an acute myocardial infarction or unstable angina) during the index hospitalization (from the presentation to the ED to the discharge from the hospital). Logistic regression modeling was performed to examine the association of risk scores and coronary plaque burden to the outcome of ACS. Unadjusted models were individually fitted for the coronary plaque burden and for Goldman, Sanchis, TIMI, and chest pain scores. In adjusted analyses, the authors tested whether the association between risk scores and ACS persisted after controlling for the coronary plaque burden. The prognostic discriminatory capacity of the risk scores and plaque burden for ACS was assessed using c-statistics. The differences in area under the receiver-operating characteristic curve (AUC) and c-statistics were tested by performing the −2 log likelihood ratio test of nested models. A p value <0.05 was considered statistically significant.
Among 368 subjects, 31 (8%) subjects were diagnosed with ACS. Goldman (AUC = 0.61), Sanchis (AUC = 0.71), and TIMI (AUC = 0.63) had modest discriminatory capacity for the diagnosis of ACS. Plaque burden was the strongest predictor of ACS (AUC = 0.86; p < 0.05 for all comparisons with individual risk scores). The combination of plaque burden and risk scores improved prediction of ACS (plaque + Goldman AUC = 0.88, plaque + Sanchis AUC = 0.90, plaque + TIMI AUC = 0.88; p < 0.01 for all comparisons with coronary plaque burden alone).
Risk scores (Goldman, Sanchis, TIMI) have modest discriminatory capacity and coronary plaque burden has good discriminatory capacity for the diagnosis of ACS in patients with acute chest pain. The combined information of risk scores and plaque burden significantly improves the discriminatory capacity for the diagnosis of ACS.
PMCID: PMC3424404  PMID: 22849339
9.  Low-Loss Transmission Lines for High-Power Terahertz Radiation 
Applications of high-power Terahertz (THz) sources require low-loss transmission lines to minimize loss, prevent overheating and preserve the purity of the transmission mode. Concepts for THz transmission lines are reviewed with special emphasis on overmoded, metallic, corrugated transmission lines. Using the fundamental HE11 mode, these transmission lines have been successfully implemented with very low-loss at high average power levels on plasma heating experiments and THz dynamic nuclear polarization (DNP) nuclear magnetic resonance (NMR) experiments. Loss in these lines occurs directly, due to ohmic loss in the fundamental mode, and indirectly, due to mode conversion into high order modes whose ohmic loss increases as the square of the mode index. An analytic expression is derived for ohmic loss in the modes of a corrugated, metallic waveguide, including loss on both the waveguide inner surfaces and grooves. Simulations of loss with the numerical code HFSS are in good agreement with the analytic expression. Experimental tests were conducted to determine the loss of the HE11 mode in a 19 mm diameter, helically-tapped, three meter long brass waveguide with a design frequency of 330 GHz. The measured loss at 250 GHz was 0.029 ± 0.009 dB/m using a vector network analyzer approach and 0.047 ± 0.01 dB/m using a radiometer. The experimental results are in reasonable agreement with theory. These values of loss, amounting to about 1% or less per meter, are acceptable for the DNP NMR application. Loss in a practical transmission line may be much higher than the loss calculated for the HE11 mode due to mode conversion to higher order modes caused by waveguide imperfections or miter bends.
PMCID: PMC3498493  PMID: 23162673
Terahertz; High power; Transmission line; Waveguide; Gyrotron
Retina (Philadelphia, Pa.)  2010;30(1):140-145.
The purpose of this study was to determine the effect on intraocular pressure (IOP) and visual acuity of treating uveitis-related hypotony in patients with vitrectomy and intravitreal silicone oil injection.
Patients who underwent pars plana vitrectomy and silicone oil injection for uveitis-associated hypotony treatment were identified retrospectively. The primary outcome was maintaining an IOP of ≥5 mmHg. Visual acuity improvement was defined as an increase in ≥2 lines of acuity.
Twelve eyes of 10 patients were identified. Median preoperative IOP was 2 mmHg (range: 0–7 mmHg). Two of 12 eyes had an IOP of ≥5 mmHg at presentation. The number of eyes with an IOP of ≥5 mmHg was 7 of 12 eyes (58%) at 1 month, 4 of 12 eyes (33%) at 3 months, 6 of 12 eyes (50%) at 6 months, and 3 of 9 eyes (33%) at 1 year. Five of 12 eyes (42%) were reinjected between 1 and 3 times with silicone oil for recurring hypotony. Median presenting Snellen visual acuity was counting fingers (range: 20/125 to light perception). Seven of 9 eyes (78%) maintained their preoperative vision at 1 year.
Intraocular pressure elevated modestly in most patients in this series. However, results were often transient, and some eyes required repeated silicone oil injections. Although silicone oil is reasonable to consider for the treatment and maintenance of IOP in patients with ocular hypotony secondary to uveitis, better treatments are needed.
PMCID: PMC3695593  PMID: 19823108
hypotony; silicone oil; uveitis
11.  Continuous-Wave Operation of a Frequency-Tunable 460-GHz Second-Harmonic Gyrotron for Enhanced Nuclear Magnetic Resonance 
The design, operation, and characterization of a continuous-wave (CW) tunable second-harmonic 460-GHz gyrotron are reported. The gyrotron is intended to be used as a submillimeter-wave source for 700-MHz nuclear magnetic resonance experiments with sensitivity enhanced by dynamic nuclear polarization. The gyrotron operates in the whispering-gallery mode TE11,2 and has generated 16 W of output power with a 13-kV 100-mA electron beam. The start oscillation current measured over a range of magnetic field values is in good agreement with theoretical start currents obtained from linear theory for successive high-order axial modes TE11,2,q. The minimum start current is 27 mA. Power and frequency tuning measurements as a function of the electron cyclotron frequency have also been carried out. A smooth frequency tuning range of 1 GHz was obtained for the operating second-harmonic mode either by magnetic field tuning or beam voltage tuning. Long-term CW operation was evaluated during an uninterrupted period of 48 h, where the gyrotron output power and frequency were kept stable to within ±0.7% and ±6 ppm, respectively, by a computerized control system. Proper operation of an internal quasi-optical mode converter implemented to transform the operating whispering-gallery mode to a Gaussian-like beam was also verified. Based on the images of the gyrotron output beam taken with a pyroelectric camera, the Gaussian-like mode content of the output beam was computed to be 92% with an ellipticity of 12%.
PMCID: PMC3677787  PMID: 23761938
Dynamic nuclear polarization (DNP); nuclear magnetic resonance (NMR); second cyclotron harmonic; submillimeter wave; terahertz; tunable gyrotron
12.  Incremental Diagnostic Value of Regional Left Ventricular Function Over Coronary Assessment by Cardiac Computed Tomography for the Detection of Acute Coronary Syndrome in Patients with Acute Chest Pain – From The ROMICAT Trial 
The incremental value of regional left ventricular function (LVF) over coronary assessment to detect acute coronary syndrome (ACS) is uncertain.
Methods and Results
We analyzed 356 patients (mean age 53±12 years, 62% male) with acute chest pain and inconclusive initial ED evaluation. Patients underwent 64-slice contrast-enhanced cardiac CT prior to hospital admission. Caregivers and patients remained blinded to the results. Regional LVF and presence of coronary atherosclerotic plaque and significant stenosis (>50%) were separately assessed by two independent readers. Incremental value of regional LVF to predict ACS was determined in the entire cohort and in subgroups of patients with nonobstructive CAD, inconclusive assessment for stenosis (defined as inability to exclude significant stenosis due to calcium or motion), and significant stenosis. During their index hospitalization, 31 patients were ultimately diagnosed with ACS (8 myocardial infarction, 22 unstable angina), of which 74% (23 patients) had regional LV dysfunction. Adding regional LVF resulted in a 10% increase in sensitivity to detect ACS by cardiac CT (87%, 95%-confidence interval [CI]: 70–96%) and significantly improved the overall accuracy (c-statistic: 0.88 vs. 0.94 and 0.79 vs. 0.88, for extent of plaque and presence of stenosis; respectively; both p<0.03). The diagnostic accuracy of regional LVF for detection of ACS has 89% sensitivity and 86% specificity in patients with significant stenosis (n=33) and 60% sensitivity and 86% specificity in patients with inconclusive coronary CTA (n=33).
Regional LVF assessment at rest improves diagnostic accuracy for ACS in patients with acute chest pain, especially in those with coronary artery disease and thus may be helpful to guide further management in patients at intermediate risk for ACS.
Clinical Trial Registration
URL: Unique Identifier: NCT00990262
PMCID: PMC3662235  PMID: 20484542
computed tomography; left ventricular function; acute coronary syndrome; emergency department
13.  Divergence, convergence, and the ancestry of feral populations in the domestic rock pigeon 
Current Biology  2012;22(4):302-308.
Domestic pigeons are spectacularly diverse and exhibit variation in more traits than any other bird species [1]. In The Origin of Species, Charles Darwin repeatedly calls attention to the striking variation among domestic pigeon breeds – generated by thousands of years of artificial selection on a single species by human breeders – as a model for the process of natural divergence among wild populations and species [2]. Darwin proposed a morphology-based classification of domestic pigeon breeds [3], but the relationships among major groups of breeds and their geographic origins remain poorly understood [4, 5]. We used a large, geographically diverse sample of 361 individuals from 70 domestic pigeon breeds and two free-living populations to determine genetic relationships within this species. We found unexpected relationships among phenotypically divergent breeds that imply convergent evolution of derived traits in several breed groups. Our findings also illuminate the geographic origins of breed groups in India and the Middle East, and suggest that racing breeds have made substantial contributions to feral pigeon populations.
PMCID: PMC3288640  PMID: 22264611
14.  Effects of Messages Emphasizing Environmental Determinants of Obesity on Intentions to Engage in Diet and Exercise Behaviors 
Reducing rates of obesity will require interventions that influence both individual decisions and environmental factors through changes in public policy. Previous work indicates that messages emphasizing environmental determinants increases support for public policies, but some suspect this strategy may undermine motivation to engage in diet and exercise.
Study 1 involved 485 adults recruited from a shopping mall in New York. Study 2 involved 718 adult members of a Web-based national panel of US adults. Respondents in both studies were randomly assigned to read a story that emphasized environmental determinants of health or a control condition. The stories varied in the extent to which they described the story character as taking personal responsibility for weight management. Logistic regression and ordered logit models were used to test for differences in intentions to engage in diet and exercise behaviors based on which story the participant read. Analyses were also performed separately by participants’ weight status.
In both studies, messages that acknowledged personal responsibility while emphasizing environmental causes of obesity increased intentions to engage in healthy behavior for at least 1 weight status group.
Emphasizing factors outside of personal control appears to enhance rather than undermine motivations to engage in healthy diet and exercise behavior.
PMCID: PMC3864704  PMID: 24331282
15.  Clinical decision support in small community practice settings: a case study 
Using an eight-dimensional model for studying socio-technical systems, a multidisciplinary team of investigators identified barriers and facilitators to clinical decision support (CDS) implementation in a community setting, the Mid-Valley Independent Physicians Association in the Salem, Oregon area. The team used the Rapid Assessment Process, which included nine formal interviews with CDS stakeholders, and observation of 27 clinicians. The research team, which has studied 21 healthcare sites of various sizes over the past 12 years, believes this site is an excellent example of an organization which is using a commercially available electronic-health-record system with CDS well. The eight-dimensional model proved useful as an organizing structure for the evaluation.
PMCID: PMC3197983  PMID: 21504995
Developing/using computerized provider order entry; improving the education and skills training of health professionals; developing/using clinical decision support (other than diagnostic) and guideline systems; social/organizational study; qualitative/ethnographic field study; knowledge representations; classical experimental and quasi-experimental study methods (lab and field); designing usable (responsive) resources and systems; statistical analysis of large datasets; discovery and text and data mining methods; automated learning; human–computer interaction and human-centered computing; qualitative/ethnographic field study; clincal decision support; machine learning; knowledge bases; clinical decision support; ambulatory care; ambulatory care
16.  Branch Retinal Artery Occlusion Caused by Toxoplasmosis in an Adolescent 
Case Reports in Ophthalmology  2012;3(3):333-338.
Branch retinal artery occlusion (BRAO), while not uncommon in elderly patient populations, is rare in children and adolescents. We report a case of a BRAO secondary to toxoplasmosis in this demographic.
A previously healthy 17-year-old male developed a unilateral BRAO in conjunction with inflammation and increased intraocular pressure. Family history was positive for cerebrovascular accidents in multiple family members at relatively young ages. The patient had a hypercoagulable workup as well as a cardiovascular workup which were both normal. A rheumatologic workup was unremarkable. By 3 weeks, a patch of retinitis was more easily distinguished from the BRAO and the diagnosis of ocular toxoplasmosis was made. Treatment was started with prednisone and azithromycin with subsequent improvement in vision. Toxoplasma antibody levels were elevated for IgG and negative for IgM, IgA, and IgE. The etiology of the BRAO was attributed to ocular toxoplasmosis.
Vascular occlusions are rare in toxoplasmosis. This is the third case report of a BRAO in a patient in the pediatric population. The diagnosis of ocular toxoplasmosis should be considered in young patients with retinal artery occlusions associated with inflammation.
PMCID: PMC3493006  PMID: 23139678
Toxoplasmosis; Branch retinal artery occlusion; Vascular occlusion; Uveitis; Inflammation
17.  A model of host response to a multi-stage pathogen 
Journal of mathematical biology  2010;63(2):201-227.
We model the immune surveillance of a pathogen which passes through n immunologically distinct stages. The biological parameters of this system induce a partial order on the stages, and this, in turn, determines which stages will be subject to immune regulation. This corresponds to the system's unique asymptotically stable fixed point.
PMCID: PMC3095709  PMID: 20890604
Models of microepidemics; Multi-stage pathogen; Host–pathogen interaction; Mathematical models in immunology
18.  Medical radiation exposure and risk of retinoblastoma resulting from new germline RB1 mutation 
Although ionizing radiation induces germline mutations in animals, human studies of radiation-exposed populations have not detected an effect. We conducted a case-control study of sporadic bilateral retinoblastoma, which results from a new germline RB1 mutation, to investigate gonadal radiation exposure of parents from medical sources before their child's conception. Parents of 206 cases from 9 North American institutions and 269 controls participated; fathers of 184 cases and 223 friend and relative controls and mothers of 204 cases and 260 controls provided information in telephone interviews on their medical radiation exposure. Cases provided DNA for RB1 mutation testing. Of common procedures, lower GI series conferred the highest estimated dose to testes and ovaries. Paternal history of lower GI series was associated with increased risk of retinoblastoma in the child (matched odds ratio (OR)=3.6, 95% confidence interval (CI) 1.2, 11.2, 2-sided P=0.02), as was estimated total testicular dose from all procedures combined (OR for highest dose=3.9, 95% CI 1.2, 14.4, P =0.02). Maternal history of lower GI series was also associated with increased risk (OR=7.6, 95% CI 2.8, 20.7, P <0.001) as was estimated total dose (OR for highest dose=3.0, 95% CI 1.4, 7.0, P =0.005). The RB1 mutation spectrum in cases of exposed parents did not differ from that of other cases. Some animal and human data support our findings of an association of gonadal radiation exposure in men and women with new germline RB1 mutation detectable in their children, although bias, confounding, and/or chance may also explain the results.
PMCID: PMC3124307  PMID: 20648557
germline mutation; ionizing radiation; retinoblastoma; case-control studies; pediatric cancer
19.  Transcriptional repressors, corepressors and chromatin modifying enzymes in T cell development 
Cytokine  2010;53(3):271-281.
Gene expression is regulated by the combined action of transcriptional activators and transcriptional repressors. Transcriptional repressors function by recruiting corepressor complexes containing histone-modifying enzymes to specific sites within DNA. Chromatin modifying complexes are subsequently recruited, either directly by transcriptional repressors, or indirectly via corepressor complexes and/or histone modifications, to remodel chromatin into either a transcription-friendly ‘open’ form or an inhibitory ‘closed’ form. Transcriptional repressors, corepressors and chromatin modifying complexes play critical roles throughout T cell development. Here, we highlight those genes that function to repress transcription and that have been shown to be required for T cell development.
PMCID: PMC3049313  PMID: 21163671
20.  Recommended practices for computerized clinical decision support and knowledge management in community settings: a qualitative study 
The purpose of this study was to identify recommended practices for computerized clinical decision support (CDS) development and implementation and for knowledge management (KM) processes in ambulatory clinics and community hospitals using commercial or locally developed systems in the U.S.
Guided by the Multiple Perspectives Framework, the authors conducted ethnographic field studies at two community hospitals and five ambulatory clinic organizations across the U.S. Using a Rapid Assessment Process, a multidisciplinary research team: gathered preliminary assessment data; conducted on-site interviews, observations, and field surveys; analyzed data using both template and grounded methods; and developed universal themes. A panel of experts produced recommended practices.
The team identified ten themes related to CDS and KM. These include: 1) workflow; 2) knowledge management; 3) data as a foundation for CDS; 4) user computer interaction; 5) measurement and metrics; 6) governance; 7) translation for collaboration; 8) the meaning of CDS; 9) roles of special, essential people; and 10) communication, training, and support. Experts developed recommendations about each theme. The original Multiple Perspectives framework was modified to make explicit a new theoretical construct, that of Translational Interaction.
These ten themes represent areas that need attention if a clinic or community hospital plans to implement and successfully utilize CDS. In addition, they have implications for workforce education, research, and national-level policy development. The Translational Interaction construct could guide future applied informatics research endeavors.
PMCID: PMC3334687  PMID: 22333210
21.  Aberrant Right Subclavian Artery–Esophageal Fistula and Severe Gastrointestinal Bleeding after Surgical Correction of Scimitar Syndrome 
Texas Heart Institute Journal  2012;39(4):571-574.
Scimitar syndrome and gastrointestinal bleeding from an aberrant right subclavian artery–esophageal fistula are each extremely rare. Although scimitar syndrome and aberrant right subclavian artery are typically asymptomatic in adults, fistulous connection between the aberrant artery and the esophagus is associated with a poor prognosis. Outcomes are contingent upon timely diagnosis and prompt surgical repair. Prolonged nasogastric and endotracheal intubation can lead to gastrointestinal bleeding in patients who have an aberrant right subclavian artery or other vascular ring. We recommend neither embolization nor the use of endovascular stents as anything other than a temporizing measure in the management of aberrant right subclavian artery injury. These methods can stop acute hemorrhage; however, sentinel bleeding will eventually occur and require definitive ligation.
We report the case of a 57-year-old woman in whom an aberrant right subclavian artery–esophageal fistula developed after surgical correction of symptomatic scimitar syndrome. Massive gastrointestinal bleeding resulted from prolonged nasogastric and endotracheal intubation. To our knowledge, this is the first report of aberrant right subclavian artery and scimitar syndrome in the same patient, and the 4th report of a patient's surviving a fistula between the aberrant artery and the esophagus.
PMCID: PMC3423267  PMID: 22949782
Esophageal fistula/complications/diagnosis/etiology/surgery; gastrointestinal hemorrhage/diagnosis/etiology; heart defects, congenital/pathology; hematemesis/etiology; intubation/adverse effects; scimitar syndrome/complications/diagnosis; subclavian artery/abnormalities/surgery; treatment outcome
22.  A Novel Persistence Associated EBV miRNA Expression Profile Is Disrupted in Neoplasia 
PLoS Pathogens  2011;7(8):e1002193.
We have performed the first extensive profiling of Epstein-Barr virus (EBV) miRNAs on in vivo derived normal and neoplastic infected tissues. We describe a unique pattern of viral miRNA expression by normal infected cells in vivo expressing restricted viral latency programs (germinal center: Latency II and memory B: Latency I/0). This includes the complete absence of 15 of the 34 miRNAs profiled. These consist of 12 BART miRNAs (including approximately half of Cluster 2) and 3 of the 4 BHRF1 miRNAs. All but 2 of these absent miRNAs become expressed during EBV driven growth (Latency III). Furthermore, EBV driven growth is accompanied by a 5–10 fold down regulation in the level of the BART miRNAs expressed in germinal center and memory B cells. Therefore, Latency III also expresses a unique pattern of viral miRNAs. We refer to the miRNAs that are specifically expressed in EBV driven growth as the Latency III associated miRNAs. In EBV associated tumors that employ Latency I or II (Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric carcinoma), the Latency III associated BART but not BHRF1 miRNAs are up regulated. Thus BART miRNA expression is deregulated in the EBV associated tumors. This is the first demonstration that Latency III specific genes (the Latency III associated BARTs) can be expressed in these tumors. The EBV associated tumors demonstrate very similar patterns of miRNA expression yet were readily distinguished when the expression data were analyzed either by heat-map/clustering or principal component analysis. Systematic analysis revealed that the information distinguishing the tumor types was redundant and distributed across all the miRNAs. This resembles “secret sharing” algorithms where information can be distributed among a large number of recipients in such a way that any combination of a small number of recipients is able to understand the message. Biologically, this may be a consequence of functional redundancy between the miRNAs.
Author Summary
miRNAs are small (∼22 bp) RNAs. They play central roles in many cellular processes. Epstein-Barr virus (EBV) is an important human pathogen that establishes persistent infection in nearly all humans and is associated with several common forms of cancer. To achieve persistent infection, the virus infects B cells and uses a series of discrete transcription programs to drive these B cells to become memory B cells – the site of long term persistent infection. It was the first human virus found to express miRNAs of which there are at least 40. The functions of a few of these miRNAs are known but their expression in latently infected normal and neoplastic tissues in vivo have not been described. Here we have profiled EBV miRNAs in a wide range of infected normal and neoplastic tissue. We demonstrate that there are indeed latency program specific patterns of viral miRNA expression and that these patterns are disrupted in EBV associated tumors implicating EBV miRNAs both in long term persistence and in oncogenesis.
PMCID: PMC3161978  PMID: 21901094
23.  MicroRNA Expression Data Reveals a Signature of Kidney Damage following Ischemia Reperfusion Injury 
PLoS ONE  2011;6(8):e23011.
Ischemia reperfusion injury (IRI) is a leading cause of acute kidney injury, a common problem worldwide associated with significant morbidity and mortality. We have recently examined the role of microRNAs (miRs) in renal IRI using expression profiling. Here we conducted mathematical analyses to determine if differential expression of miRs can be used to define a biomarker of renal IRI. Principal component analysis (PCA) was combined with spherical geometry to determine whether samples that underwent renal injury as a result of IRI can be distinguished from controls based on alterations in miR expression using our data set consisting of time series measuring 571 miRs. Using PCA, we examined whether changes in miR expression in the kidney following IRI have a distinct direction when compared to controls based on the trajectory of the first three principal components (PCs) for our time series. We then used Monte Carlo methods and spherical geometry to assess the statistical significance of these directions. We hypothesized that if IRI and control samples exhibit distinct directions, then miR expression can be used as a biomarker of injury. Our data reveal that the pattern of miR expression in the kidney following IRI has a distinct direction based on the trajectory of the first three PCs and can be distinguished from changes observed in sham controls. Analyses of samples from immunodeficient mice indicated that the changes in miR expression observed following IRI were lymphocyte independent, and therefore represent a kidney intrinsic response to injury. Together, these data strongly support the notion that IRI results in distinct changes in miR expression that can be used as a biomarker of injury.
PMCID: PMC3156120  PMID: 21887224
24.  Comparison of Post-Processing Techniques for the Detection of Perfusion Defects by Cardiac Computed Tomography in Patients Presenting with Acute ST Segment Elevation Myocardial Infarction 
Despite rapid advances in cardiac computed tomography (CT), a strategy for optimal visualization of perfusion abnormalities on CT has yet to be validated.
To evaluate the performance of several post-processing techniques of source data sets to detect and characterize perfusion defects in acute myocardial infarctions with cardiac CT.
Twenty-one subjects (18 men; 60 ± 13 years) that were successfully treated with percutaneous coronary intervention for ST-segment myocardial infarction underwent 64-slice cardiac CT and 1.5 Tesla cardiac MRI scans following revascularization. Delayed enhancement MRI images were analyzed to identify the location of infarcted myocardium. Contiguous short axis images of the left ventricular myocardium were created from the CT source images using 0.75mm multiplanar reconstruction (MPR), 5mm MPR, 5mm maximal intensity projection (MIP), and 5mm minimum intensity projection (MinIP) techniques. Segments already confirmed to contain infarction by MRI were then evaluated qualitatively and quantitatively with CT.
Overall, 143 myocardial segments were analyzed. On qualitative analysis, the MinIP and thick MPR techniques had greater visibility and definition than the thin MPR and MIP techniques (p < 0.001). On quantitative analysis, the absolute difference in Hounsfield Unit (HU) attenuation between normal and infarcted segments was significantly greater for the MinIP (65.4 HU) and thin MPR (61.2 HU) techniques. However, the relative difference in HU attenuation was significantly greatest for the MinIP technique alone (95%, p < 0.001). Contrast to noise was greatest for the MinIP (4.2) and thick MPR (4.1) techniques (p < 0.001).
The results of our current investigation found that MinIP and thick MPR detected infarcted myocardium with greater visibility and definition than MIP and thin MPR.
PMCID: PMC2898897  PMID: 20579617
Cardiac computed tomography; post processing techniques; ST-segment myocardial infarction; minimum intensity projection
The activation of T cells and the initiation of an immune response is tightly controlled by both positive and negative regulators. Two adaptors which function as negative regulators of T cell activation are ALX and LAX. ALX constitutively associates with LAX in T cells, and T cells from mice deficient in ALX and LAX display similar hyper-responsiveness upon T cell receptor (TCR)/CD28 stimulation, including increased production of interleukin-2. During T cell activation, ALX is inducibly phosphorylated, however the site of ALX phosphorylation had not been previously identified and the role of phosphorylation in the inhibitory function of ALX was not known. Here, using mass spectrometry, we demonstrate that ALX is phosphorylated on a serine at position 318. Substitution of alanine for serine at this position (ALX S318A) leads to an abrogation of the mobility shift in ALX induced upon TCR/CD28 stimulation. However, ALX S318A retained the ability to bind to and stimulate tyrosine phosphorylation of LAX. In addition, overexpression of ALX S318A inhibited RE/AP activation upon TCR/CD28 stimulation to a similar extent as wild type ALX. Therefore, although ALX is inducibly phosphorylated upon TCR/CD28 stimulation, this phosphorylation is not required for ALX to inhibit T cell activation.
PMCID: PMC2897073  PMID: 20471366
T cell; adaptor; ALX; phosphorylation

Results 1-25 (63)